Dispute Flares Inside FDA Over Safety of Popular Blood-Pressure Drugs

The top-selling class of blood-pressure drugs is under attack from an unusual source: a senior regulator at the Food and Drug Administration.

Bucking his bosses, Thomas A. Marciniak is seeking stronger warnings about the drugs known as angiotensin receptor blockers, or ARBs, according to internal documents reviewed by The Wall Street Journal.

The drugs, which are taken by millions of people and generated $7.6 billion in U.S. sales in 2012, may be linked to higher cancer rates, Dr. Marciniak argues, a view shared by some outside doctors. Top FDA officials say evidence doesn't support a link.

The debate over ARBs highlights the question of whether the U.S. drug-safety agency devotes enough effort to examining the safety of long-marketed blockbusters as it focuses on new drugs. In a rare rebellion by an FDA reviewer, Dr. Marciniak has clashed with his bosses over his desire to spend time on ARB safety, instead of just on new-drug applications.

Ellis Unger, chief of the drug-evaluation division that includes Dr. Marciniak, called the complaints a "diversion," and said in an interview, "We have no reason to tell the public anything new."

In a 2010 study published in Lancet Oncology, Ilke Sipahi and colleagues at University Hospitals in Cleveland looked at five studies involving 68,402 patients and found that people taking ARBs had an 11% greater risk of new cancer overall and a 25% greater risk of new lung cancer, compared with patients who didn't get the drugs.

But within a year, the FDA gave the all-clear signal, saying its own analysis found "no increase in risk" from taking ARBs. Europe's drug regulator also dismissed the cancer concerns.

Dr. Marciniak wasn't persuaded. In its analysis, the FDA combined different studies to look at more patients, multiplying its statistical power to find possible side effects from the drugs, a technique called meta-analysis. If the original studies have flaws, however, meta-analyses can simply compound the problem, researchers say.

That is what happened to the FDA, says Dr. Marciniak, who warned others in the agency that taking results tabulated by companies was likely to produce unreliable results: "Garbage in, garbage out," he wrote.

Among other things, Dr. Marciniak said in an internal analysis viewed by the Journal that the FDA meta-analysis didn't count cases of "lung carcinomas" as lung cancers, which they are.

While such vocal dissent by FDA reviewers is rare, internal disputes about drugs or medical devices have occasionally arisen. In 2008, nine employees in the FDA's device division wrote to members of Congress saying the division's leaders were ignoring safety issues when approving devices.

After the FDA's 2011 verdict dismissing cancer concerns about ARBs, Dr. Marciniak decided to go through the raw data of the drug studies, patient by patient. By this March, he had concluded that lung-cancer risk increased by about 24% in ARB patients, compared with patients taking a placebo or other drugs, a figure that he said was statistically significant. He found that in 10 of the 11 studies he examined, there were more lung cancer cases in the ARB-treated patients than in the control group.

He sent a memo to senior FDA officials, saying: "The FDA needs to inform patients and physicians about the ARB lung-cancer risks. The FDA must act now."

Dr. Unger, the FDA division chief, said in the interview that he didn't agree. He said Dr. Marciniak's use of raw data from patients could include as cancers some patient-reported ailments that doctors might not agree are cancers, making the FDA's own research more credible.

Daiichi-Sankyo, Merck, Sanofi and Bristol-Myers said they haven't seen Dr. Marciniak's data and couldn't comment. Novartis said it did an "initial analysis" of studies of its Diovan and found "no increased risk." Other drug makers didn't respond to requests for comment.

Some of the drugs are known generically as valsartan, olmesartan, losartan, telmisartan, irbesartan and candesartan.

Dr. Marciniak's analysis didn't include data from trials on some ARB drugs, including Benicar, but he concluded "that the increased incidence of lung cancers with ARB use is likely a class effect of ARBs" and that it would be "inappropriate" to classify specific ARBs as safe due to a "lack of adequate studies."

Opinion is divided among outside doctors familiar with the ARB studies. "I have no doubt that ARBs increase cancer risk," Dr. Sipahi, an author of the 2010 study, told The Wall Street Journal.

Cleveland Clinic cardiologist Steven Nissen, a frequent critic of the FDA, said the FDA "has a huge advantage over academic researchers, of having access to patient-level data" that it hasn't fully examined. "Until I see such a rigorous analysis, I remain concerned about the ARB cancer problems," he said.

Eric J. Topol, a cardiologist and chief academic officer at Scripps Health in La Jolla, Calif., said, "My impression is there isn't a relationship between ARBs and cancer, but there could be one with a low frequency. It's not something easily detectable."

Dr. Marciniak specialized in cancer during his residency at the Mayo Clinic and spent a decade at the National Cancer Institute before coming to the FDA.

The debate he has sparked over ARBs has been accompanied by a dispute with his boss over how Dr. Marciniak spent his time.

Writing to Dr. Marciniak last August, Dr. Unger discouraged a safety investigation of the ARB drugs. "This would represent a lot of man-hours, so I have to assume that there is a paucity of work in the [cardio-renal] division at this point," he wrote, "or that you will be doing this mostly after-hours."

Dr. Marciniak responded on Aug. 31. "You are faced with a serious, unanswered question of whether drugs taken by millions of Americans increase cancer rates, and you're concerned about 62 to 93 man-days for my entire plan?" he asked. He went ahead with his inquiry.

In another email exchange, Dr. Unger wrote that even if Dr. Marciniak "found an increased cancer risk of [30%], I doubt there would be much enthusiasm for basing a regulatory decision (labeling or otherwise) on that."

Dr. Marciniak shot back, "Astonishingly, you would ignore a 30% increase in cancer rates for any drug, much less drugs for which there are many alternatives?"

Dr. Unger said in the interview he meant that if the 30% cancer increase weren't convincingly proven, the FDA wouldn't act.

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